Abstract Candida albicans is uniquely associated as a commensal component of the microbiota of most humans, without harm to most of us, yet it causes a range of infections from mild to life- threatening, based on the immune status of the host. The interaction between C. albicans and mammalian phagocytes is critical, and the Candida-macrophage co-culture has become a valuable model to uncover specific adaptations that promote virulence and commensalism. To further probe the novel biology of this interaction, we used transcriptional profiling to identify fungal genes induced upon phagocytosis. While some of these have recognizable functions, mostly in metabolism (a known response to phagocytosis), more than half the induced genes are uncharacterized and not widely conserved. A surprising number of these genes are quite small and missed in early annotations. Given the uniqueness of the C. albicans-human association, this set of genes is likely enriched for adaptations of C. albicans to host niches. In proof of this principle, we have mutated three of these genes and all three have host-relevant phenotypes, with one as a novel cell wall-associated microadhesin required for adhesion to biotic and abiotic surfaces and for virulence in mouse models. We propose that it clusters conventional adhesins into heterogeneous complexes on the cell surface that strengthens binding to substrates. Two others have antioxidant properties, again despite being quite small proteins (68 and 99 amino acids). These are therefore unique mediators of functions appreciated to be critical for Candida virulence (adhesion and oxidative stress resistance). We propose studies to discern the mechanistic details underlying both phenotypes. Based on the successes of our preliminary genetic analysis, we propose a larger-scale effort to generate a mutant library of all of the uncharacterized macrophage-induced genes and test them in multiple in vitro, ex vivo, and in vivo assays. The strength of this proposal is in our expertise in analyzing this critical host-pathogen interaction, our thorough genetic methods and screening protocols, and the use of multiple animal models. The innovative potential is significant given the focus on novel genes and novel biology at the host-pathogen interface. The outcome of this proposal is a deeper and broader understanding of the genetic functions that are required for commensalism and pathogenicity in fungi.